The goal of the proposed research is to elucidate the genetic control mechanism governing the antibody variability and the application of this knowledge to combat inherited diseases. Amino acid sequence determination and analyses of inherited antigenic determinants (i.e., Gm, Am, Inv markers) will be carried out on immunoglobulins from normal individuals as well as patients with multiple myeloma, Waldenstrom's macroglobulinemia, hypogammaglobulinemia, idiopathic cold agglutinin syndrome and various other immunodeficient conditions. Data obtained from these studies will be essential for the understanding of the following: 1. More than one gene is involved in the synthesis of each immunoglobulin polypeptide chain. 2. The nature of association between constant and variable region genes. 3. The switch of a given variable region gene from constant region gene of a micron chain to that of a gamma or alpha chain during the course of an immune response. 4. The phenomena of specific gene activation and allelic exclusion in immunoglobulin producing cells. 5. The correlation between amino acid sequences of hypervariable regions and antigen combing sites in antibodies of a given specificity. 6. The phylogenetic relationship of immunoglobulin structural genes and the origin of immune mechanism.